SARS-CoV-2 NEWS! Study Reveals Stress-Activated Kinase NUAK2 As Key Player In SARS-CoV-2 Cell Entry
Reducing NUAK2 Abundance Or Kinase Activity Impaired SARS-CoV-2 Particle Binding And Internalization By Decreasing Cell Surface Levels Of Viral Receptors
: In a remarkable collaboration between Heidelberg University, the University of Applied Sciences-Bingen am Rhein, the University of Bristol, ETH Zürich, the German Cancer Research Center, and the German Center for Infection Research, a team of German-led researchers has made a significant breakthrough in understanding the mechanisms behind SARS-CoV-2 entry into host cells. Their study sheds light on the role of stress-activated kinase NUAK2 as a novel host-dependency factor for the virus, with potential implications for future therapeutic interventions.
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had a devastating impact worldwide, driving an urgent need to unravel the intricacies of the virus's infection biology and pathogenesis. The study team focused on the endoplasmic reticulum (ER), an organelle crucial for SARS-CoV-2 replication. By inducing ER stress and triggering the unfolded protein response (UPR), the virus remodels the ER to form replication organelles.
The UPR is a cellular program that aims to restore homeostasis in response to ER stress. It involves sensor proteins, such as IRE1α, PERK, and ATF6, which detect and transmit signals to effector molecules, activating transcription factors that regulate gene expression. While previous studies have shown that SARS-CoV-2 infection can modulate UPR activation, the specific role of downstream UPR factors in viral replication has remained poorly understood.
One protein of interest, NUAK2, belongs to the family of AMP-activated protein kinases (AMPKs) and plays a role in responding to metabolic and physiological stress. NUAK2 is involved in regulating the actin cytoskeleton and stress fibers, processes critical for cellular motility and polarity.
Shockingly, the study team found that NUAK2 is a host-dependency factor induced by UPR during SARS-CoV-2 infection, as well as during infections with related coronaviruses HCoV-229E and MERS-CoV.
By reducing the abundance or kinase activity of NUAK2, the study team observed a decrease in SARS-CoV-2 particle binding and internalization. This effect was attributed to the modulation of the actin cytoskeleton and a subsequent reduction in cell surface levels of viral receptors, including ACE2, which is crucial for viral entry. Furthermore, NUAK2 levels were found to increase in both infected and non-infected bystander cells, indicating the potential for intercellular transmission of UPR and viral spread.
Corresponding and lead author, Dr Vibhu Prasad from the Department of Infectious Diseases at Heidelberg University told
reporters at TMN, “The findings of this study provide valuable insights into the molecular mechanisms underlying SARS-CoV-2 entry and highlight NUAK2 as a promising target for future therapeutic interventions. By understanding the role of NUAK2 in regulating viral receptor abundance and trafficking, researchers may develop strategies to disrupt the entry process, ultimately inhibiting viral replication and spread.”
While further studies are needed to fully elucidate the regulatory mechanisms of NUAK2 and its interplay with the UPR pathway, this study represents a crucial step forward in our understanding of SARS-CoV-2 infection. The insights gained from this research have the potential to inform the development of effective treatments and preventive measures against COVID-19, bringing us one step closer to overcoming this global health crisis.
The study findings were published in the peer reviewed journal: Molecular Cell.
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